Cannabinoid Control of Olfactory Processes: The Where Matters

Olfaction has a direct influence on behavior and cognitive processes. There are different neuromodulatory systems in olfactory circuits that control the sensory information flowing through the rest of the brain. The presence of the cannabinoid type-1 (CB1) receptor, (the main cannabinoid receptor in the brain), has been shown for more than 20 years in different brain olfactory areas. However, only over the last decade have we started to know the specific cellular mechanisms that link cannabinoid signaling to olfactory processing and the control of behavior. In this review, we aim to summarize and discuss our current knowledge about the presence of CB1 receptors, and the function of the endocannabinoid system in the regulation of different olfactory brain circuits and related behaviors.This research was funded by Fondation pour la Recherche Médicale (FRM, FDT20170436845) (to G.T.); The Basque Government (ITI230-19), Red de Trastornos Adictivos, Instituto de Salud Carlos III (ISC-III) and European Regional Development Funds-European Union (ERDF-EU; grant RD16/0017/0012), MINECO/FEDER, UE (SAF2015-65034-R) (to P.G.); EU–FP7 (PAINCAGE, HEALTH-603191), European Research Council (Endofood, ERC–2010–StG–260515; CannaPreg, ERC-2014-PoC-640923, Micabra) (to G.M.); Ikerbasque (The Basque Foundation for Science) and MINECO (Ministerio de Economía y Competitividad) PGC2018-093990-A-I00 (to E.S.-G.)

Subcellular specificity of cannabinoid effects in striatonigral circuits

Recent advances in neuroscience have positioned brain circuits as key units in controlling behavior, implying that their positive or negative modulation necessarily leads to specific behavioral outcomes. However, emerging evidence suggests that the activation or inhibition of specific brain circuits can actually produce multimodal behavioral outcomes. This study shows that activation of a receptor at different subcellular locations in the same neuronal circuit can determine distinct behaviors. Pharmacological activation of type 1 cannabinoid (CB1) receptors in the striatonigral circuit elicits both antinociception and catalepsy in mice. The decrease in nociception depends on the activation of plasma membrane-residing CB1 receptors (pmCB1), leading to the inhibition of cytosolic PKA activity and substance P release. By contrast, mitochondrial-associated CB1 receptors (mtCB1) located at the same terminals mediate cannabinoid-induced catalepsy through the decrease in intra-mitochondrial PKA-dependent cellular respiration and synaptic transmission. Thus, subcellular-specific CB1 receptor signaling within striatonigral circuits determines multimodal control of behavior

Roles of cannabinoid type-1 receptors in the anterior piriform cortex

Impliquée dans de nombreuses fonctions comportementales, l'olfaction joue un rôle majeur quant à l'orientation de nos actions. Les odeurs communiquent avec le système nerveux central par l'intermédiaire de récepteurs situés dans l'épithélium olfactif du nez qui génèrent des signaux neuronaux, transmis et traités dans de nombreuses régions du cerveau. En particulier, le cortex piriforme antérieur (CPa) est une région olfactive importante impliquée dans la perception et l'intégration des odeurs. Étant donné le rôle du principal récepteur aux cannabinoïdes de type 1 (CB1) dans les fonctions sensorielles et les processus de mémoire, nous avons émis l'hypothèse que ces récepteurs pourraient moduler le traitement des odeurs dans le CPa. Pour ce faire, en combinant des approches anatomiques, électrophysiologiques et pharmacologiques, nous avons d'abord caractérisé la répartition des récepteurs CB1 et évalué leur capacité à réguler les circuits du CPa. Nous avons observé que ces récepteurs sont principalement exprimés dans les interneurones GABAergiques et que leur activation régule la transmission et la plasticité inhibitrice. Puis, nous avons cherché à déterminer le rôle et l'impact des récepteurs CB1 dans le traitement des odeurs dans le CPa. Grâce à une technique d'imagerie calcique in vivo, nous avons montré que l'altération de la signalisation des récepteurs CB1 affecte l'activité des neurones du CPa en réponse aux odeurs. En agissant très semblablement sur les circuits inhibiteurs locaux, nous avons mis en évidence que le fonctionnement physiologique des récepteurs CB1 dans le CPa est nécessaire pour le rappel d’une information olfactive apprise dans un contexte appétitif mais pas aversif. De façon générale, ces travaux permettent de mieux comprendre comment les récepteurs CB1 modulent les processus olfactifs dans le CPa.Being involved in many behavioral functions, olfaction has powerful influence in guiding our actions. Odors communicate with the central nervous system via specialized receptors in the nose olfactory epithelium that generate neuronal signals, which in turn are eventually distributed and processed in many brain regions. In particular, the anterior piriform cortex (aPC) is an important olfactory area involved in perception and integration of odors. Given the extended role of the main cannabinoid type-1 (CB1) receptor in sensory and memory brain functions, we hypothesized that CB1 receptors could modulate odor processing in the aPC. To this aim, using a combination of anatomical, electrophysiological, and pharmacological approaches, we first characterized the distribution of CB1 receptors and their ability to regulate aPC circuits. We found that CB1 receptors are mainly expressed in GABAergic interneurons where their activation regulates inhibitory transmission and plasticity. Then, we evaluated the role and the impact of CB1 receptor modulation on odor-related aPC processing. In vivo calcium imaging revealed that odor-evoked aPC activity is affected by alteration of CB1 receptor signaling. Additionally, we demonstrated that physiological aPC-CB1 receptors functioning is necessary for retrieve appetitive but not aversive olfactory memory, likely through modulation of local inhibitory circuits. Overall, this work contribute to a better understanding of how CB1 receptors modulate olfactory processes in the aPC

Rôles des récepteurs cannabinoïdes de type 1 dans le cortex piriforme antérieur

Being involved in many behavioral functions, olfaction has powerful influence in guiding our actions. Odors communicate with the central nervous system via specialized receptors in the nose olfactory epithelium that generate neuronal signals, which in turn are eventually distributed and processed in many brain regions. In particular, the anterior piriform cortex (aPC) is an important olfactory area involved in perception and integration of odors. Given the extended role of the main cannabinoid type-1 (CB1) receptor in sensory and memory brain functions, we hypothesized that CB1 receptors could modulate odor processing in the aPC. To this aim, using a combination of anatomical, electrophysiological, and pharmacological approaches, we first characterized the distribution of CB1 receptors and their ability to regulate aPC circuits. We found that CB1 receptors are mainly expressed in GABAergic interneurons where their activation regulates inhibitory transmission and plasticity. Then, we evaluated the role and the impact of CB1 receptor modulation on odor-related aPC processing. In vivo calcium imaging revealed that odor-evoked aPC activity is affected by alteration of CB1 receptor signaling. Additionally, we demonstrated that physiological aPC-CB1 receptors functioning is necessary for retrieve appetitive but not aversive olfactory memory, likely through modulation of local inhibitory circuits. Overall, this work contribute to a better understanding of how CB1 receptors modulate olfactory processes in the aPC.Impliquée dans de nombreuses fonctions comportementales, l'olfaction joue un rôle majeur quant à l'orientation de nos actions. Les odeurs communiquent avec le système nerveux central par l'intermédiaire de récepteurs situés dans l'épithélium olfactif du nez qui génèrent des signaux neuronaux, transmis et traités dans de nombreuses régions du cerveau. En particulier, le cortex piriforme antérieur (CPa) est une région olfactive importante impliquée dans la perception et l'intégration des odeurs. Étant donné le rôle du principal récepteur aux cannabinoïdes de type 1 (CB1) dans les fonctions sensorielles et les processus de mémoire, nous avons émis l'hypothèse que ces récepteurs pourraient moduler le traitement des odeurs dans le CPa. Pour ce faire, en combinant des approches anatomiques, électrophysiologiques et pharmacologiques, nous avons d'abord caractérisé la répartition des récepteurs CB1 et évalué leur capacité à réguler les circuits du CPa. Nous avons observé que ces récepteurs sont principalement exprimés dans les interneurones GABAergiques et que leur activation régule la transmission et la plasticité inhibitrice. Puis, nous avons cherché à déterminer le rôle et l'impact des récepteurs CB1 dans le traitement des odeurs dans le CPa. Grâce à une technique d'imagerie calcique in vivo, nous avons montré que l'altération de la signalisation des récepteurs CB1 affecte l'activité des neurones du CPa en réponse aux odeurs. En agissant très semblablement sur les circuits inhibiteurs locaux, nous avons mis en évidence que le fonctionnement physiologique des récepteurs CB1 dans le CPa est nécessaire pour le rappel d’une information olfactive apprise dans un contexte appétitif mais pas aversif. De façon générale, ces travaux permettent de mieux comprendre comment les récepteurs CB1 modulent les processus olfactifs dans le CPa

Synaptic functions of type-1 cannabinoid receptors in inhibitory circuits of the anterior piriform cortex

In the olfactory system, the endocannabinoid system (ECS) regulates sensory perception and memory. A major structure involved in these processes is the anterior piriform cortex (aPC), but the impact of ECS signaling in aPC circuitry is still scantly characterized. Using ex vivo patch clamp experiments in mice and neuroanatomical approaches, we show that the two major forms of ECS-dependent synaptic plasticity, namely depolarization-dependent suppression of inhibition (DSI) and long-term depression of inhibitory transmission (iLTD) are present in the aPC. Interestingly, iLTD expression depends on layer localization of the inhibitory neurons associated with the expression of the neuropeptide cholecystokinin. Conversely, the decrease of inhibitory transmission induced by exogenous cannabinoid agonists or DSI do not seem to be impacted by these factors. Altogether, these results indicate that CB1 receptors exert an anatomically specific and differential control of inhibitory plasticity in the aPC, likely involved in spatiotemporal regulation of olfactory processes

Quantitative assessment of hippocampal network dynamics by combining Voltage Sensitive Dye Imaging and Optimal Transportation Theory

For many years, voltage sensitive dye imaging (VSDI) has enabled the fruitful analysis of neuronal transmission by monitoring the spreading of neuronal signals. Although useful, the display of diffusion of neuronal depolarization provides insufficient information in the quest for a greater understanding of neuronal computation in brain function. Here, we propose the optimal mass transportation theory as a model to describe the dynamics of neuronal activity. More precisely, we use the solution of an -Monge–Kantorovich problem to model VSDI data, to extract the velocity and overall orientation of depolarization spreading in anatomically defined brain areas. The main advantage of this approach over earlier models (e.g. optical flow) is that the solution does not rely on intrinsic approximations or on additional arbitrary parameters, as shown from simple signal propagation examples. As proof of concept application of our model, we found that in the mouse hippocampal CA1 network, increasing Schaffers collaterals stimulation intensity leads to an increased VSDI-recorded depolarization associated with dramatic decreases in velocity and divergence of signal spreading. In addition, the pharmacological activation of cannabinoid type 1 receptors (CB1) leads to slight but significant decreases in neuronal depolarization and velocity of signal spreading in a region-specific manner within the CA1, indicating the reliability of the approach to identify subtle changes in circuit activity. Overall, our study introduces a novel approach for the analysis of optical imaging data, potentially highlighting new region-specific features of neuronal networks dynamics

Endogenous cannabinoids in the piriform cortex tune olfactory perception

Abstract Sensory perception depends on interactions between external inputs transduced by peripheral sensory organs and internal network dynamics generated by central neuronal circuits. In the sensory cortex, desynchronized network states associate with high signal-to-noise ratio stimulus-evoked responses and heightened perception. Cannabinoid-type-1-receptors (CB1Rs) - which influence network coordination in the hippocampus - are present in anterior piriform cortex (aPC), a sensory paleocortex supporting olfactory perception. Yet, how CB1Rs shape aPC network activity and affect odor perception is unknown. Using pharmacological manipulations coupled with multi-electrode recordings or fiber photometry in the aPC of freely moving male mice, we show that systemic CB1R blockade as well as local drug infusion increases the amplitude of gamma oscillations in aPC, while simultaneously reducing the occurrence of synchronized population events involving aPC excitatory neurons. In animals exposed to odor sources, blockade of CB1Rs reduces correlation among aPC excitatory units and lowers behavioral olfactory detection thresholds. These results suggest that endogenous endocannabinoid signaling promotes synchronized population events and dampen gamma oscillations in the aPC which results in a reduced sensitivity to external sensory inputs

Chemogenetic stimulation of adult neurogenesis, and not neonatal neurogenesis, is sufficient to improve long-term memory accuracy

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CB1 Receptors in the anterior piriform cortex control odor preference memory

The retrieval of odor-related memories shapes animal behavior. The anterior piriform cortex (aPC) is the largest part of the olfactory cortex, and it plays important roles in olfactory processing and memory. However, it is still unclear whether specific cellular mechanisms in the aPC control olfactory memory, depending on the appetitive or aversive nature of the stimuli involved. Cannabinoid-type 1 (CB1) receptors are present in the aPC (aPC-CB1), but their potential impact on olfactory memory was never explored. Here, we used a combination of behavioral, genetic, anatomical, and electrophysiological approaches to characterize the functions of aPC-CB1 receptors in the regulation of appetitive and aversive olfactory memory. Pharmacological blockade or genetic deletion of aPC-CB1 receptors specifically impaired the retrieval of conditioned odor preference (COP). Interestingly, expression of conditioned odor aversion (COA) was unaffected by local CB1 receptor blockade, indicating that the role of aPC endocannabinoid signaling is selective for retrieval of appetitive memory. Anatomical investigations revealed that CB1 receptors are highly expressed on aPC GABAergic interneurons, and ex vivo electrophysiological recordings showed that their pharmacological activation reduces miniature inhibitory post-synaptic currents (mIPSCs) onto aPC semilunar (SL), but not pyramidal principal neurons. COP retrieval, but not COA, was associated with a specific CB1-receptor-dependent decrease of mIPSCs in SL cells. Altogether, these data indicate that aPC-CB1 receptor-dependent mechanisms physiologically control the retrieval of olfactory memory, depending on odor valence and engaging modulation of local inhibitory transmission.Dissection des mécanismes hypothalamiques impliqués dans la détection du statut nutritionnel et régulation de la prise alimentaire via les interactions entre mTORC1, les mélanocortines et les endocannabinoïdes.Représentation sensorielle lors d'états psychotiquesRecepteurs aux cannabinoides dans le codage visuel corticalRecepteurs aux cannabinoides dans le codage visuel corticalNeurocircuitry of endocannabinoid regulation of food intakeDevelopment of pregnenolone derivatives as allosteric inhibitors of CB1 cannabinoid receptors for thetreatment of schizophrenia and psychotic syndrome